HDL binding

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

The nascent HDL particles change shape and composition as they acquire additional free cholesterol by passive cellular diffusion of free cholesterol from cell membranes or from other plasma lipoproteins. HDL surface-localized LCAT progressively converts the free cholesterol on the surface of the particles to cholesterol ester, which occupies the core of the lipoprotein particle. This process converts the shape of the HDL particles from discoidal to spherical. The lipid unloading of HDL in the liver follows at least two pathways. In the first route, the cholesterol ester transfer protein (CETP) mediates cholesterol ester transfer from HDL to VLDL and LDL in exchange for triglyceride LDL in turn are taken up by the liver via the LDL receptor. In the second route, HDL binds to the scavenger receptor Bl, and cholesterol esters are selectively taken into the liver cells without internalization of HDL proteins (Fig. 15-2). 

High-density lipoprotein functions as a shuttle that moves cholesterol throughout the body. HDL binds and esterifies cholesterol released from the peripheral tissues and then transfers cholesteryl esters to the liver or to tissues that use cholesterol to synthesize steroid hormones. A specific receptor mediates the docking of the HDL to these tissues. The exact nature of the protective effect of HDL levels is not known however, a possible mechanism is discussed in Section... 

HDL, like LDL, is a cholesterol-rich particle, and is distinct from the other lipoprotein classes in that it does not contain apoB. HDL levels are inversely correlated with risk for atherosclerosis (Wilson et al., 1988). Nascent HDL particles are produced by direct synthesis (Hamilton, 1984), and excess surface remnants from chylomicrons and VLDL produced during the action of lipoprotein lipase (as noted above) enter the HDL density class. HDL appears to be involved in delivery of cholesterol to steroidogenic tissues as well as the removal of excess cholesterol from peripheral tissues and excretion from the system. This HDL-mediated removal of cholesterol has been termed reverse cholesterol transport (Glomset, 1968). Although apolipoproteins present in HDLs are cleared by the liver, the reverse cholesterol transport pathway has never been directly demonstrated. HDL can remove cholesterol from tissues, a process that may be partially mediated by interaction with a putative HDL receptor, with apoA-I as the ligand for that receptor (Oram el ai, 1983). The existence of an HDL receptor remains controversial saturable HDL binding may not be mediated by a specific apolipoprotein ligand and may not even be required for transfer of cholesterol from cells to... 

One important experimental result was available, the quantitative measurement of the fraction of each secondary structural element by circular dichroism (CD) on purified lipid-protein complexes. This provided a constraint that allowed a careful evaluation of the secondary structure predictions derived from the various approaches, some of which were developed for water-soluble proteins and therefore of uncertain reliability for proteins in a lipid environment. The data from these analyses were combined using an integrated prediction method to arrive at a consensus secondary structure model for each protein. The integrated method involved 36 steps, with independent predictions at each step. The final model was based on an evaluation of the various predictions, with judicious intervention by the authors. As an aid to developing the appropriate weighting of all the data, they carried out the analysis for apoE-3 without reference to the available crystal structure (Wilson et al., 1991), then used the known structure of the HDL-binding amino-terminal domain of apoE-3 as feedback to reevaluate the weighting. 

It has been proposed that HDL binds to certain cells via high-affinity saturable binding sites (Gwynne and Strauss, 1982 Oram et al., 1981) and that this binding may be mediated by a membrane protein (Oram and... 

HDL binding sites have been reported in several tissues. The interaction appears to be mediated by apo A-I. However, a lipid-lipid interaction may mediate HDL-to-cell binding in fibroblasts and smooth muscle cells. In macrophages, binding occurs via apo A-I. HDL in the macrophage then gains apo E and cholesterol from intracellular lipid droplets. The apo E-enriched and cholesterol-enriched HDL are then secreted (retroendocytosis) into the plasma. An increase in the apo E concentration increases HDL uptake by the liver. The liver and kidneys are believed to be the principal organs for HDL catabolism. 

C-II Chylomicrons, VLDL, (IDL), HDL Binds to and activates lipoprotein lipase... 

After HDL binding to SR-BI D, cholesteryl esters in the core are selectively transferred to a cell s membrane B and then into the cytosol B by as-yet-unknown mechanisms. The remaining lipid-... 

Fig. 4. Model showing the interactions between the endothelial cell surface, triacylglycerol-rich lipoproteins, apo C2, and lipoprotein lipase (LPL). Two LPL molecules are shown reacting with the same VLDL particle. These are representative of the multiple LPLs that probably react with each triacylglycerol-rich lipoprotein. The location of the recently identified glycosylphosphatidylinositol-anchored HDL binding protein-1 within the substrate-lipase complex has not yet been identified.

HDL binding to SR class B type I (SR-BI) on the cell surface mediates the transfer of its cholesteryl esters to the cell and subsequent release of the lipid-depleted HDL into... 

Activates lipoprotein lipase when the chylomicrons and VLDLs turive at their target tissue In chylomicrons, VLDLs and HDLs Binds to receptor... 

In contrast, HDL binding to liver membranes is very much dependent on the content of Apo E. Treatment of rats with 17-alpha-ethinylestradiol (EE) does not... 

We could isolate two HDL-binding proteins a 78-kDa protein from human placenta and a llOrkDa HDL-binding protein from human leukocytes.investigations concerning the ligand specificity of the 110-kDa protein revealed that the affinity for... 

Phospholipid transfer protein (PLTP) (carrier protein that shuttles between lipoproteins to redistribute lipids) deficiency in mice is associated with decreased atherosclerosis despite decreased HDL levels. Two mechanisms are involved decreased Apo B-containing lipoprotein production and levels, and increased antioxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, DM, and CAD (reviewed in ref. 429). PLTP mRNA protein expression and activity was increased by cholesterol loading of macrophages. PLTP increased HDL binding to biglycan, suggesting a role in lipoprotein retention on ECM (430). 

Do HDL levels correlate with the rate of reverse cholesterol transport Studies of the expression of the SR-Bl receptor provide an answer to this question. When HDL binds to SR-B1 at the plasma membrane of the hepatocyte, it unloads its cholesterol ester cargo. The lipid-depleted apo-Al then is cleared from the circulation, in part by the kidney. High levels of SR-Bl therefore lead to low HDL... 

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